This invention concerns new phenoxypropanolamines, the pharmaceutical compositions that contain them, a process for their preparation and intermediate products in this process.
BE 902897 describes aryloxypropanolamines with a 4-piperidininyl-1group substituted on the amine, these compounds having beta-blocking and alpha-blocking activity.
J. Org. Chem., 1988, 63:889:894 describes other aryloxypropanolamines having a 4-piperidininyl-1 group substituted on the amine.
It has now been found that phenoxypropanolamines having a 1-(pyrid-2-yl)-piperidine-4-yl radical on the amine have an agonistic activity with regard to adrenergic xcex23 receptors.
Accordingly the present invention concerns, in one of its aspects, phenoxypropanolamines of formula (Ia) 
R1a represents hydrogen, an xe2x80x94S(O)z xe2x80x94(C1-C4)Alk group, a xe2x80x94CO(C1-C4)Alk group, an xe2x80x94NHSO2 xe2x80x94(C1-C4)Alk group, an NHCO(C1-C4)Alk group, a 2-furyl group or a halogen;
R2 represents hydrogen, or a (C1-C4)Alk group, a (C1-C4)alkoxyl group, a halogen, xe2x80x94COOH, xe2x80x94COO(xe2x80x94(C1-C4)Alk, xe2x80x94CNxe2x80x94CONR3R4xe2x80x94NO2, xe2x80x94SO2NH2, xe2x80x94NHSO2 (C1-C4)Alk;
m and n are independently 0, 1 or 2;
R3 and R4 independently represent hydrogen or a (C1-C4)Alk group;
Z is 1 or 2;
and their salts or solvates.
According to another of its aspects, the invention concerns compounds of formula (I): 
wherein
R1 represents hydrogen, an xe2x80x94S(O),xe2x80x94(C1-C4)Alk group, a xe2x80x94CO(C1-C4)Alk group or an xe2x80x94NHSO2xe2x80x94(C1-C4)Alk group;
R2 represents hydrogen or a (C1-C4)Alk group, a (C1-C4)alkoxyl group, a halogen, xe2x80x94COOH, xe2x80x94COO(C1-C4)Alk;
m and n are independently 0, 1 or 2;
R3 and R4 independently represent hydrogen or a (C-C4)Alk group;
Z is 1 or 2 and their salts or solvates.
In the present description the term xe2x80x9c(C1-C4)Alkxe2x80x9d designates a monovalent radical of a saturated hydrocarbon in C1-C4 with a straight or branched chain.
The salts of compounds of formula (I) according to the present invention comprise equally the addition salts with inorganic or organic acids that are pharmaceutically acceptable such as hydrochloride, hydrobromate, sulphate, hydrogen-sulphate, dihydrogenphosphate, citrate, maleate, tartrate, fumarate, gluconate, methane sulphonate, 2-naphthalene sulphonate, and so on, and the addition salts that permit separation or suitable crystallisation of compounds of formula (I), such as the picrate, oxalate or the addition salts with optically active acids, for example the camphor sulphonic acids and the mandelic or substituted mandelic acids.
Moreover, when the compounds of formula (I) and (Ia) possess a free carboxyl group the salts also comprise the salts with inorganic bases, preferably those with alkaline metals such as sodium or potassium, or with organic bases.
The optically pure stereo-isomers, together with the mixtures of isomers of compounds of formula (I) and (Ia), due to asymmetrical carbons or to the sulfinyl group, in the meaning of R1a or R1, in any proportions, form part of the present invention.
Preferred compounds of the present invention comprise the compounds of formula (I) and (Ia) in which the R2 group is at position 5 of the pyridine.
Other preferred compounds comprise the compounds of formula (I) or (la) wherein the R2 group is in position 6 of the pyridine.
Other preferred compounds are those in which the (C1-C4) Alk group is a methyl or ethyl group.
Other preferred compounds are those in which R2 is one of the following: xe2x80x94COOH, xe2x80x94COO(C1-C4)Alk, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CONR2R3, or xe2x80x94NHSO2(C1-C4)Alk.
Other preferred compounds are those in which R2 is a halogen, notably chlorine.
Other preferred compounds are those in which n and m are zero.
The compounds of formula (I) and (Ia) can be prepared by treating a compound of formula (II) 
in which R1b is R1a or R1 as indicated above, Pxe2x80x2 is a protective group and X is a group of formula (a) or (b) 
where Gp is an initial group such as tosylate, mesylate or a halogen, with an amine of formula (III). 
wherein n, m and R2 are as defined above, with the Pxe2x80x2 group split off by the usual methods and as appropriate converting the compound of formula (I) or (Ia) obtained into one of these salts.
More particularly, the reaction between the compounds of formulas (I) and (III) is carried out in an organic solvent, for example a lower alcohol such as methanol, ethanol or isopropanol; dimethylsulphoxide; a linear or cyclic ether; an amide such as dimethylformamide or dimethylacetamide; using at least equimolecular quantities of the reagents, with a slight excess of amine as appropriate.
The reaction temperature is between room temperature and the reflux temperature of the chosen solvent.
The protective groups Pxe2x80x2 can be the usual protective groups for the hydroxyl groups such as for example methoxyethoxymethyl (MEM) or benzyl.
These protective groups are split off using the normal methods for the protective group selected; for example in the case of the benzyl group by hydrogenation in the presence of a catalyst such as Pd/C in a suitable solvent; however in the case of methoxyethoxymethyl (MEM) it is possible to use an acid such as trifluoroacetic acid.
Most of the epoxides in formula (II) are compounds known in the literature or alternatively can be prepared by processes similar to those described in the literature. For example certain epoxides of formula (II) are described in WO 96/04233 and in U.S. Pat. No. 4,396,629.
The pure isomers of the compounds of formula (II) in which X is a group (a) and Rab represents the SOCH3 group, resolved to the asymmetrical carbon, are new, having been obtained for the first time as pure stereo-isomers free of other stereo-isomers or impurities.
Certain epoxides of formula (II) are new and constitute another object of the present invention.
More particularly, these are compounds of formula (IIxe2x80x2): 
wherein Pxe2x80x2 is as defined in formula (II), X is a group (a) as defined above and Y represents an atom of bromine or a 2-furyl group, their optically active isomers and their salts. They are prepared as described in examples 44 and 47.
The amines of formula (III) can be prepared by reacting appropriate pyridines of formula (IV) 
where Hal represents a halogen and R2 and m are as defined above, with a piperidine of formula (V) below 
where n is as defined above and P represents a protective group, in an organic solvent in the presence of a base, followed by splitting off the P group from the compounds of formula (VI) obtained. 
As a reaction solvent for example, it is possible to use dimethylformamide, pyridine, dimethylsulphoxide, a linear or cyclic ether or a chlorinated solvent such as dichloromethane.
As a base for example one can use an alkaline hydroxide, an alkaline carbonate such as potassium carbonate or a tertiary amine such as triethylamine.
The above condensation reaction takes a few hours, normally between 2 and 12 hours.
The reaction temperature is between room temperature and the reflux temperature for the chosen solvent.
As protective groups P it is possible to use the usual protective groups for amines, for example ter-butoxycarbonyl, acetyl, or carbobenzyloxy.
These protective groups are split off using the normal methods described for the selected protective group; for example in the case of ter-butoxycarbonyl, splitting off is normally done by acid hydrolysis.
Certain intermediate amines of a formula (III) and (VI), grouped together in formula (VII) below 
where
Pxc2x0 is hydrogen or a protective group;
nxc2x0 and mxc2x0 are 0, 1 or 2;
Rxc2x02 is a (C1-C4)Alk; (C1-C4)alkoxyl, xe2x80x94COOH, xe2x80x94COO(C1-C4)Alk, xe2x80x94CN, xe2x80x94NO2, xe2x80x94CONR3xc2x0R4xc2x0, xe2x80x94SO2NH2, or
xe2x80x94NHSO2(C1-C4)Alk;
Rxc2x03 and Rxc2x04 are hydrogen or a (C1-C4)Alk group; on condition that:
when nxc2x0 and mxc2x0 are zero, Rxc2x02 is other than methoxyl at position 6 and other than halogen in position 3 or 6 on the pyridine; when nxc2x0 is 1, mxc2x0 is 0, Rxc2x02 is other than chlorine in position 6 of the pyridine and when nxc2x0 is 0, mxc2x0 is 0 or 1, Rxc2x02 is other than methyl; and their salts, are new compounds and are a later subject of the present invention.
Particularly preferred compounds of formula (VII) are those in which Rxc2x02 is chosen from the groups xe2x80x94COOH, xe2x80x94COO(C1-C4)Alk, xe2x80x94CN, NO2, xe2x80x94CONR3xc2x0R4xc2x0, xe2x80x94SO2NH2, and xe2x80x94NHSO2(C1-C4)Alk.
Other preferred compounds of formula (VII) are those in which Rxc2x02 is at position 5 of the pyridine.
Other preferred compounds of formula (VII) are those in which nxc2x0 and mxc2x0 are zero.
Other particularly preferred compounds of formula (VII) are those in which Pxc2x0 is hydrogen.
The compounds of formula (I) have shown very strong affinity for the xcex23 receptors.
The activity of the compounds of the present invention with regard to xcex23 activity has been demonstrated by in vitro tests on the human colon using the method described in EP-B-436435 and in T. Croci et al, Br. J. Pharmacol., 1997, 122: 139P.
It was noted in particular that the compounds of formula (I) and (Ia) are much more active on the isolated colon than on the auricle and the trachea.
These surprising properties of the compounds of formula (I) and (Ia) suggest that they could be used as xcex23 action drugs.
Moreover the compounds of formula (I) and (Ia) are only slightly toxic; in particular their acute toxicity is compatible with their use as drugs for treating diseases where compounds having an affinity for the ###3 receptor are applied. The compounds of formula (I) and (Ia), together with their pharmaceutically acceptable salts, may therefore be indicated for example for the treatment of gastro-intestinal diseases such as irritable bowel syndrome, as modulators of intestinal peristalsis such as the lipolytics, and anti-obesity, anti-diabetic, psychotropic, anti-glaucoma, healing and anti-depressant agents, as an inhibitor of uterine contractions, as tocolytic agents to prevent or delay premature births, and for treating and/or prophylaxis of dysmenorrhoea.
The use of compounds of formula (I) and (Ia) above, and of their pharmaceutically acceptable salts and solvates for preparing the above drugs constitutes a later aspect of the present invention.
For such a purpose, mammals that necessitate such treatment are administered an effective quantity of a compound of formula (I) or (Ia) or of one of its pharmaceutically acceptable salts and solvates.
The compounds of formula (I) and (Ia) above and their pharmaceutically acceptable salts and solvates can be used in daily doses of 0.01 to 20 mg per kilo of body weight of the mammal to be treated, preferably in daily doses of 0.1 to 10 mg/kg. In man, the dose can vary for preference from 0.5 mg to 1500 mg a day, notably from 2.5 to 500 mg according to the age of the patient, the type of treatment (prophylactic or curative) and the gravity of the disease. The compounds of formula (I) and (Ia) are usually administered in dose units of 0.1 to 500 mg, preferably 0.5 to 100 mg of active principle, from 1 to 5 times a day.
The said dose units are preferably formulated in pharmaceutical compounds in which the active principle is mixed with a pharmaceutical excipient.
Thus according to another of its aspects, the present invention concerns pharmaceutical compositions in which the active principle is a compound of formula of (I) or (Ia) above or one of its pharmaceutically acceptable salts and solvates.
In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, transdermal or rectal administration, the active ingredients of formula (I) or (Ia) above, and their pharmaceutically acceptable salts and solvates, can be administered in unitary forms mixed with conventional pharmaceutical media, to animals and man, for treating the above-mentioned diseases. The appropriate unitary forms of administration comprise the forms given by mouth such tablets, capsules, powders, granules and oral solutions or suspensions, the sublingual and buccal forms of administration, the subcutaneous, intramuscular or intravenous forms of administration, the local forms of administration and the rectal forms of administration.
When a solid composition is prepared in the form of tablets, the principal active ingredient is mixed with the pharmaceutical vector such as gelatine, starch, lactose, magnesium stearate, talc, gum arabic or similar. The tablets may be coated with saccharose or other suitable materials or they may be processed in such a way that their activity is extended or delayed so that they release a predetermined quantity of active principle on a continuous basis.
A capsule preparation is obtained by mixing the active ingredient with a diluant and pouring the mixture produced into soft or rigid capsules.
A preparation in the form of syrup or tincture can contain the active ingredient together with a sweetener, preferably of the low-calorie variety, methylparaben and propylparaben as antiseptics, together with a flavour agent and an appropriate colour.
Powders and granules that are dispersible in water may contain the active ingredient mixed with dispersion agents or wetting agents, or suspension agents, such as polyvinylpyrrolidone, and with sweeteners or flavour correctors.
For local administration, the active principle is mixed with an excipient for preparing creams or unguents or it is dissolved in a vector for administration into the eye, for example in the form of eye drops.
For rectal administration, suppositories are used that are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.
For administration into the digestive tract, aqueous suspensions, saline solutions or sterile injectable solutions are used that contain dispersion agents and/or pharmacologically compatible wetting agents, for example propylene glycol or butylene glycol.
The active principle may also be formulated in the form of microcapsules, possibly with one or more vectors or additives.
According to another of its aspects, the present invention concerns a method of treating diseases that are improved by a ###3-agonistic action, which involves administering a compound of formula (I) or (Ia) or one of its pharmaceutically acceptable salts or solvates.
The compounds of formula (I) and (Ia), notably the compounds (I) and (Ia) marked by an isotope, can also be used as laboratory tools in biochemical tests.
The compounds of formula (I) and (Ia) bind to the ###3-adrenergic receptor. These compounds can therefore be used an ordinary binding test, that utilise an organic tissue in which this receptor is particularly abundant, and the quantity of compound (I) or (Ia) displaced by a test compound is measured, in order to evaluate the affinity of the said compound for the bonding sites of this particular receptor.
Another specific object of the present invention is therefore a reagent that can be used in biochemical tests that comprises at least one compound of formula (I) or (Ia) appropriately marked.
The following examples give a better illustration of the invention.
25 g (0.13 mole) of 4-amino-1-benzylpiperidine, 36.2 ml (0.26 mole) of triethylamine and 31.2 g (0.143 mole) of di-ter-butyl-dicarbonate are mixed at room temperature for 2 hours in 200 ml of dimethylformamide. The mixture is poured into water, extracted with ethyl acetate, washed with water and the product obtained crystallised in 200 ml of isopropyl ether. This produces 33 g of 1-benzyl-4-ter-butoxycarbonylamino-piperidine which is hydrogenated in a mixture of 200 ml of ethanol and 100 ml of tetrahydrofurane in the presence of 3 g of 10% Pd/C. After filtering the catalyst, the named compound is isolated; M. P. 157-160xc2x0 C.
Proceed as for preparation 1, but using 4-aminomethyl-1-benzylamine instead of the 4-amino-1-benzylamine, producing the named compound M. P. 105-107xc2x0 C.